title: Pyripyropene A, an acyl-coenzyme A:cholesterol acyltransferase 2-selective inhibitor, attenuates hypercholesterolemia and atherosclerosis in murine models of hyperlipidemia.
abstract: OBJECTIVE
  Pyripyropene A (PPPA) of fungal origin is the first compound that has been found to strongly and selectively inhibit acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) isozyme activity in vitro. The purpose of the present study was to investigate in vivo efficacy of the ACAT2-selective inhibitor in atherosclerosis.
  
  
  RESULTS
  PPPA treatment (10 to 100 mg/kg) caused 30.5±4.7% to 55.8±3.3% inhibition of the cholesterol absorption from the mouse intestine. When PPPA (10 to 50 mg/kg per day) was orally administered to apolipoprotein E-knockout mice for 12 weeks, the levels of plasma cholesterol, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) and hepatic cholesterol content were lowered. Furthermore, the ratio of cholesteryl oleate (exclusively synthesized in hepatic ACAT2) to cholesteryl linoleate in VLDL- and LDL-derived cholesteryl ester decreased, indicating that hepatic ACAT2 activity was inhibited by PPPA. PPPA-treated mice had reduced atherogenic lesion areas that were lowered by 26.2±3.7% to 46±3.8% in the aortae and by 18.9±3.6% to 37.6±6.0% in the hearts.
  
  
  CONCLUSIONS
  Our findings indicate that ACAT2-selective inhibition in the intestine and the liver can be effective against atherosclerosis and that PPPA appears to be a potential antiatherogenic lead compound. This study is the first demonstration of the in vivo efficacy of PPPA, an ACAT2-selective inhibitor, in atherosclerosis. PPPA-treated atherogenic mice showed a decrease in intestinal cholesterol absorption and cholesterol and cholesteryl oleate levels in both LDL and VLDL, resulting in protection of atherosclerosis development.
authors.affiliation: Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Ohshiro
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsuda
authors.forename: Kent
authors.initials: K
authors.lastname: Sakai
authors.forename: Chiara
authors.initials: C
authors.lastname: Degirolamo
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yagyu
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002788:Cholesterol Esters / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D007408:Intestinal Absorption / Q000187:drug effects; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D002788:Cholesterol Esters; D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011725:Pyridines; D012717:Sesquiterpenes; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C082792:pyripyropene A; C014409:cholesteryl oleate; C021976:cholesteryl linoleate